The long-term goal of this project is to determine the role of tracheal and pharyngeal sensory feedback in the regulation of cough and swallow. Our central hypothesis is that an aspiration event produces a series of coughs and swallows which are expressed in various behavioral interaction patterns, and that there are decipherable rules that regulate the various patterns of expression. Cough and swallow are airway protective behaviors. The pharyngeal phase of swallow prevents aspiration of oral material (saliva, food and liquid), by epiglottal movement, laryngeal adduction, and clearing the mouth and pharynx. Cough is an aspiration- response behavior that clears material from the airway. Coordination of these behaviors is vital to protect the airway from further aspiration-promoting events, such as a swallow occurring during the inspiratory phase of cough. The peripheral inputs, operational characteristics, and primary strategies that coordinate cough and swallow are unknown. This lack of information impedes understanding of the deficits in airway protection, with co-occurrence of dystussia and dysphagia, which occurs with diseases such as Parkinson's disease and Alzheimer's disease. The Specific Aims of the project are: 1) Identify the operational principles that govern the coordination of cough and swallow motor patterns following activation of tracheal and pharyngeal afferents during an aspiration event; 2) Develop a predictive computational distributed network model of the central influence of tracheal sensory pathways on the expression of cough and swallow; and 3) Identify the role of neurons in the reticular formation in processing tracheal and pharyngeal afferent feedback on cough and swallow. Our preliminary data demonstrates a modulatory effect of sensory feedback of the production of cough and swallow. Stimulation of tracheal afferents by an aspiration stimulus increases the magnitude of swallows, providing evidence of airway feedback-induced increased pharyngeal clearance. We have observed a distinct phase restriction relationship that governs when swallow occurs in response to pharyngeal afferent feedback during cough. In the first aim, we will perturb the cough and swallow motor patterns by protocols that simultaneously stimulate tracheal and pharyngeal afferents. Additionally, we will selectively manipulate afferent input through bilateral electrical stimulation of the superior laryngeal nerve. In aim 2, we will test a model of the central effects of tracheal afferent stimulation on the coordination of cough and swallow using network simulation tools to allow both discrete integrate and fire (IF) populations and hybrid populations that incorporate Hodgkin-Huxley style equations for sub-threshold currents. In aim 3, we will: 1) record from neurons in the reticular formation using a multi-electrode array to obtain multiple-spike train data during: a) the selective stimulation of the trachea or pharynx to elicit cough or swallow; b) simultaneous stimulation of the trachea and pharynx to elicit coordinated cough and swallow; and c) selective manipulation of cough and swallow using electrical stimulation of the superior laryngeal nerve; 2) test an acute model of dystussia and dysphagia induced by microinjection of the endogenous excitatory amino acid antagonist, kynurenic acid, into the medial reticular formation. The results of these experiments will significantly advance our understanding of the influence of airway and sensory feedback on the coordination of cough and swallow.